17. Drakopoulos S, Koukoulaki M, Apostolou T et al. Total parathyroidectomy without autotransplantation in dialysis patients and renal transplant recipients, long-term follow-up evaluation. Am J Surg 2009; 198: 178–183 18. Puccini M, Carpi A, Cupisti A et al. Total parathyroidectomy without autotransplantation for the treatment of secondary hyperparathyroidism associated with chronic kidney disease: clinical and laboratory long-term follow-up. Biomed Pharmacother 2010; 64: 359–362

19. Chan HW, Chu KH, Fung SK et al. Prospective study on dialysis patients after total parathyroidectomy without autoimplant. Nephrology (Carlton) 2010; 15: 441–447 20. Sharma J, Raggi P, Kutner N et al. Improved long-term survival of dialysis patients after near-total parathyroidectomy. J Am Coll Surg 2012; 214: 400–407 Received for publication: 13.2.2015; Accepted in revised form: 3.7.2015

Nephrol Dial Transplant (2016) 31: 111–119 doi: 10.1093/ndt/gfv249 Advance Access publication 8 July 2015

John J. Bissler1, John Christopher Kingswood2, Elżbieta Radzikowska3, Bernard A. Zonnenberg4, Michael Frost5, Noah Berkowitz11, Sara Miao11, Scott Segal11, Severine Peyrard12 and Klemens Budde9 1

St. Jude Children’s Research Hospital and Le Bonheur Children’s Hospital, University of Tennessee Health Science Center, Memphis, TN, USA,

2

Royal Sussex County Hospital, Brighton, UK, 3National Tuberculosis and Lung Diseases Research Institute, Warsaw, Poland, 4Universitair

Medisch Centrum, Utrecht, The Netherlands, 5Minnesota Epilepsy Group, St Paul, MN, USA, 6Moscow Research Institute of Pediatrics and Pediatric Surgery, Moscow, Russia, 7Medizinische Klinik und Poliklinik IV, Klinikum der Universität MüNchen, Munich, Germany, 8Osaka University Hospital, Osaka, Japan, 9Charité Universitätsmedizin, Berlin, Germany, 10Division of Child and Adolescent Psychiatry, University of Cape Town, Cape Town, South Africa, 11Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA and 12Novartis Pharmaceuticals S.A.S., Rueil-Malmaison, France

Correspondence and offprint requests to: John J. Bissler; E-mail: [email protected]

A B S T R AC T Background. Mammalian target of rapamycin (mTOR) inhibitors are recommended as first-line treatment of renal angiomyolipoma associated with tuberous sclerosis complex (TSC) or sporadic lymphangioleiomyomatosis (sporadic LAM), but follow-up is limited. Longer term efficacy and tolerability data from a Phase 3, double-blind, placebo-controlled trial are presented. Methods. Following favorable results from the primary analysis (data cutoff 30 June 2011) of the EXIST-2 trial, patients still receiving study treatment were allowed to enter an open-label extension. Everolimus was initiated at 10 mg once daily and titrated based on tolerability. The primary outcome was angiomyolipoma response rate (≥50% reduction from baseline in target lesion volumes). Safety was a secondary endpoint.

© The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

Results. As of the cutoff date (1 May 2013), 112 patients had received everolimus, and the response rate in 107 patients with angiomyolipoma (median duration of medication exposure of 28.9 months) was 54%. The proportion of patients achieving angiomyolipoma reductions of ≥30% and ≥50% increased over time, reaching 81.6% (62/76) and 64.5% (49/76), respectively, by Week 96. No everolimus-treated patients experienced renal bleeding. The long-term safety profile was consistent with previous reports; adverse events (AEs) were mostly Grade 1/2, and there were no new safety issues. The frequency of emerging AEs and severe AEs lessened over time. Conclusions. Longer term everolimus treatment appeared safe and effective in patients with TSC- or sporadic LAM-associated renal angiomyolipoma not requiring surgical intervention. Continued reduction in angiomyolipoma volume was demonstrated, and there was no angiomyolipoma-related bleeding; AEs were predictable and generally manageable. 111

ORIGINAL ARTICLE

Elena Belousova6, Matthias Sauter7, Norio Nonomura8, Susanne Brakemeier9, Petrus J. de Vries10,

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Everolimus for renal angiomyolipoma in patients with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis: extension of a randomized controlled trial

Trial Registration clinicaltrials.gov identifier. NCT00790400 (http://clinicaltrials.gov/ct2/show/NCT00790400). Keywords: everolimus, mTOR inhibitors, renal angiomyolipoma, sporadic lymphangioleiomyomatosis, tuberous sclerosis complex

Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder affecting ∼1.5 million people worldwide [1–3]. Diagnosed from birth through adulthood, TSC is characterized by growth of nonmalignant hamartomas in various organs throughout the body [4–6]. The majority of individuals with TSC have mutations in either the TSC1 or TSC2 genes [7, 8], and subsequent somatic mutation results in constitutive activation of mammalian target of rapamycin (mTOR), a critical regulator of cell growth and proliferation [9–11]. Radiological studies show that up to 80% of patients with TSC develop renal angiomyolipomas [8, 12–17], mesenchymal tumors arising from vascular pericytes [18] that are composed of dysplastic blood vessels, smooth muscle-like cells and adipose tissue [19]. The incidence of renal angiomyolipoma increases with age [15, 16], and most patients develop multiple bilateral lesions that pose a significant tumor burden on the kidneys [14]. Angiomyolipomas are slow-growing tumors but may lead to the formation of aneurysms, which can rupture, causing renal hemorrhage and shock [17, 20, 21]. Compromised renal function and end-stage renal disease have been reported [22– 25], with renal disease being a leading cause of morbidity and mortality in patients with TSC [26]. Female patients with TSC may develop lymphangioleiomyomatosis (LAM) [27–30], which may result in progressive cystic destruction of the lung parenchyma with severe impairment of lung function [31]. LAM also occurs without TSC (i.e. sporadic LAM) [12, 32]. As with sporadic angiomyolipoma [33], somatic mosaicism of TSC gene mutations has been postulated as a mechanism for sporadic LAM [34–36]. mTOR inhibitors are recommended for first-line treatment of asymptomatic, growing renal angiomyolipoma associated with TSC [37], but long-term data are limited. Everolimus, an oral mTOR inhibitor, was investigated for the treatment of renal angiomyolipoma associated with TSC or sporadic LAM in EXIST-2, a double-blind, placebo-controlled, Phase 3 trial [38]. Results from the initial treatment phase demonstrated superiority of everolimus versus placebo; the response rate ( proportion of patients with ≥50% reduction from baseline in the sum of volumes of target angiomyolipomas in the absence of progression) was 42% for everolimus and 0% for placebo [difference, 42%; 95% confidence interval (CI) 24–58%; P < 0.0001] [38]. Adverse events (AEs) were consistent with those previously reported for patients with TSC [38, 39]. Following initial positive results from the double-blind phase of the EXIST-2 trial, all patients still receiving treatment were permitted to participate in the extension phase and receive open-label everolimus. The longer term safety and efficacy results of everolimus in patients with TSC- or sporadic LAM-associated angiomyolipoma are presented here.

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Participants A complete description of study participants, design and outcomes has been published [38]. In this study, eligible patients were aged ≥18 years with ≥1 renal angiomyolipoma lesion ≥3 cm in its longest diameter, as measured by computed tomography (CT) or magnetic resonance imaging (MRI), and had a diagnosis of TSC according to consensus criteria [40, 41] or sporadic LAM, as proved with biopsy or compatible chest CT scan. Patients with angiomyolipoma requiring surgery at the time of randomization were excluded, as were those with angiomyolipoma-related bleeding or embolization during the 6 months prior. Patients with LAM exhibiting severe impairment of pulmonary function were excluded. Independent ethics committees and/or local ethics review boards approved the protocol. All patients provided written informed consent. An independent data monitoring committee performed safety reviews every 6 months, and a steering committee supervised study conduct. Study design and treatment This was a randomized, double-blind, placebo-controlled, multicenter, Phase 3 study of once-daily oral everolimus 10 mg versus placebo. Because the primary analysis, 6 months after the last participant was randomly assigned (data cutoff 30 June 2011), favored everolimus over placebo, the study was unblinded on 9 September 2011, and a preplanned open-label extension phase was launched. All patients still receiving double-blind study treatment or undergoing posttreatment evaluation could receive open-label everolimus. Patients initially randomized to everolimus continued to receive the same dose they were taking at the conclusion of the double-blind phase; those switching from placebo received everolimus 10 mg once daily. A starting dose of 10 mg was chosen as a means of providing adequate exposure to almost all patients based on dose proportionality in this adult age group. Dose modifications were to be determined clinically and were based solely on tolerability. Doses could be lowered to 5 mg/day or even to 5 mg/ every other day. In the event that a patient required coadministration of a strong cytochrome P450 3A4 or P-glycoprotein inducer, everolimus dose could be increased in 5-mg increments up to twice the currently used daily dose based on tolerability. Data cutoff for a double-blind safety analysis were 14 October 2011, and the data cutoff for this longer term extension analysis were 1 May 2013. Study outcomes The primary efficacy outcome for this analysis was response rate, defined as the proportion of patients with renal angiomyolipoma with best overall confirmed response (confirmatory second scans performed no sooner than 8 weeks later), defined as ≥50% reduction from baseline in the sum of volumes of all target lesions (≤5 largest lesions ≥1 cm in longest diameter), in the absence of new lesions ≥1 cm, kidney volume increase of >20% from nadir, and angiomyolipoma-related bleeding grade ≥2 [as defined by the National Cancer Institute Common

J.J. Bissler et al.

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ORIGINAL ARTICLE

INTRODUCTION

M AT E R I A L S A N D M E T H O D S

Long-term everolimus for renal angiomyolipoma

R E S U LT S Baseline characteristics A total of 118 patients with renal angiomyolipoma associated with TSC or sporadic LAM were enrolled from 24 centers in 11 countries between 28 April 2009 and 30 December 2010; seventy nine were randomized to everolimus and 39 to placebo in the double-blind phase. Overall, 112 patients received everolimus at any time during the study, including the 79 patients originally randomized to everolimus, and 33 patients who switched to open-label everolimus from placebo. Ninety-eight (87.5%) patients continued to receive everolimus and 14 (12.5%) had discontinued treatment at the cutoff date of 1 May 2013. The most common reason for everolimus discontinuation was AEs (including abnormal laboratory values), reported in nine patients (8%). Two patients withdrew due to administrative problems, one withdrew due to a protocol deviation and one withdrew consent. One patient (originally randomized to everolimus) with a history of intractable seizures died; the death was reported with the initial study report [38]. The median age of the 112 patients receiving everolimus was 32.2 years at baseline, and 65.2% were female (Table 1). The Table 1. Patient demographics and disease characteristics Everolimus (N = 112) Median age (range), years 32.2 (18.1–61.6) Age, n (%) ULN to 2.5× ULN; Grade 2, >2.5× ULN–5× ULN; Grade 3, >5× ULN–10× ULN; Grade 4, >10× ULN, where ULN = 2.24 mmol/L per central lab measurements.

ORIGINAL ARTICLE

percentage change in sum of volumes of target angiomyolipoma lesions was not available and patients with overall nonevaluable angiomyolipoma response.

majority of patients (59.8%) had ≥6 target lesions at baseline, and the median sum of volumes of target lesions was 92.1 cm3. More than one-third of patients (37.5%) had undergone angiomyolipoma-related surgery before initiating everolimus, and the median GFR was 85 (range 23–178) mL/min/1.73 m2. Everolimus exposure The median duration of everolimus exposure was 28.9 (range 0.5–46.2) months, and the median dose intensity was 8.91 (range 2.3–19.0) mg/day. Eighty patients (71.4%) required dose interruptions or reductions, with AEs being the most common reason (50.0 and 58.9% for dose reductions and dose interruptions, respectively). Efficacy outcomes Compared with an angiomyolipoma response rate of 42% (33/79 patients; 95% CI 31–53%) in everolimus-treated patients in the primary analysis (median treatment exposure 8.7 months) [38], the response rate increased to 54% (60/112 patients; 95% CI 44–63%); 38 patients (33.9%) had stable disease and 1 (0.9%) had disease progression as best overall response. Ninety-six of 99 evaluable patients (97.0%) experienced a reduction in the sum of volumes of target angiomyolipoma lesions relative to baseline per central radiology review (Figure 1). Of 13 (11.6%) nonevaluable patients, central review did not confirm the presence of target renal angiomyolipoma lesions in two patients; two patients had only one available baseline kidney scan and nine had ≥1 missing kidney volume measurement. Response to everolimus increased over time (Figure 2). The proportion of patients who achieved ≥50% reduction from baseline in the sum of volumes of target lesions increased from 44.2% (46/104) after 12 weeks of treatment to 64.5%

114

F I G U R E 2 : Effect of everolimus on renal angiomyolipoma volume

over time.

(49/76) at Week 96, and the proportion of patients with ≥30% reduction increased from 75.0% (78/104) after 12 weeks of treatment to 81.6% (62/76) after 96 weeks. Among the 60 patients achieving angiomyolipoma response at any time, the median time to response was 2.83 months and no progressions were observed. The duration between first response and the last radiological assessment in responders was 2.8– 38.8 months. Overall, the median time to angiomyolipoma progression was not reached, because 106/112 patients (94.6%) did not have angiomyolipoma progression (Figure 3). Estimated progression-free rates (95% CI) were 98.0% (92.1–99.5%) at 6 months, 95.7% (89.0–98.4%) at 12 months, 94.1% (86.1– 97.5%) at 24 months and 89.4% (73.2–96.0%) at 36 months. Among six patients (5.4%) with angiomyolipoma progression

J.J. Bissler et al.

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F I G U R E 1 : Best percentage change from baseline in renal angiomyolipoma volume. Excluded from the graph were patients for whom best

Safety outcomes For the 112 patients in the longer term analysis who received everolimus, the most commonly reported AEs (>25% of patients) were nasopharyngitis, stomatitis, headache, acne, hypercholesterolemia, urinary tract infection (UTI) and aphthous stomatitis (Table 2). Most AEs were Grade 1/2 in severity. Overall, 42% of patients experienced Grade 3/4 AEs, 27% were suspected to be drug related; the most frequent Grade 3 AEs regardless of relationship to study drug were amenorrhea (4.2% of the 71 at-risk female patients, i.e. those aged 18–55 years) and decreased blood phosphorus (3.6%). Grade 4 AEs were blood uric acid increased (1.8%) and convulsion, hydrocephalus, hypertensive crisis, neutropenia, pancreatic carcinoma and rhabdomyolysis (each 0.9%). Overall, 97.3% of patients reported ≥1 AE considered everolimus related, including 26.8% with Grade 3/4 AEs. Approximately one-quarter of patients (28.6%) reported serious AEs (SAEs). Fourteen patients (12.5%) experienced SAEs suspected by the investigator to be everolimus related, including infections (3.6%) and gastrointestinal disorders (2.7%). Pneumonia was reported in 1.8% of patients, and ovarian cyst was reported in 2 of 73 female patients (2.7%). After completion of the double-blind phase (safety analysis cutoff 14 October 2011), the most commonly reported AEs (>20%) were stomatitis, nasopharyngitis, hypercholesterolemia, acne, headache and cough in the everolimus group; and

Long-term everolimus for renal angiomyolipoma

Table 2. Most common (≥10% of patients) adverse events by preferred term, regardless of relationship to everolimus n (%)

Everolimus (N = 112) All grades Grade 3/4

Nasopharyngitis Stomatitis Headache Acne Hypercholesterolemia Urinary tract infection Aphthous stomatitis Amenorrheaa Cough Diarrhea Hypertension Nausea Fatigue Edema peripheral Vomiting Back pain Mouth ulceration Proteinuria Upper respiratory tract infection Blood alkaline phosphatase increased Hypophosphatemia Hyperlipidemia Leucopenia Sinusitis Abdominal pain Activated partial thromboplastin time prolonged Blood lactate dehydrogenase increased Decreased appetite Eczema Pruritus a

48 (42.9) 48 (42.9) 34 (30.4) 33 (29.5) 33 (29.5) 31 (27.7) 29 (25.9) 16 (22.5) 23 (20.5) 22 (19.6) 21 (18.8) 21 (18.8) 20 (17.9) 20 (17.9) 19 (17.0) 18 (16.1) 17 (15.2) 17 (15.2) 16 (14.3) 15 (13.4) 15 (13.4) 14 (12.5) 14 (12.5) 14 (12.5) 13 (11.6) 12 (10.7) 12 (10.7) 12 (10.7) 12 (10.7) 12 (10.7)

0 0 0 1 (0.9) 1 (0.9) 1 (0.9) 1 (0.9) 3 (4.2) 0 0 1 (0.9) 0 1 (0.9) 0 0 0 2 (1.8) 1 (0.9) 0 1 (0.9) 2 (1.8) 0 0 0 0 0 0 1 (0.9) 0 0

ORIGINAL ARTICLE

at any time during the study, two had increased size of target lesions and four had increased kidney size. Four of the six patients with progression had intermittent dose reductions or temporary dose interruptions within 6 months prior to progression, whereas two of the six were still receiving everolimus 10 mg/day. Despite the progression, all six patients were ongoing at the data cutoff of 1 May 2013. At the last follow-up, two patients had increased angiomyolipoma volume after progression, three had decreased angiomyolipoma volume after progression and one did not have a follow-up assessment.

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F I G U R E 3 : Time to renal angiomyolipoma progression.

Percentages calculated from the number of at-risk (aged 10–55 years) females (n = 71).

nasopharyngitis, headache and fatigue in the placebo group. Rates of new AEs while on treatment with everolimus decreased over time (Table 3). Most AEs reduced to incidences